Partition equilibrium of inhalation anesthetics and alcohols between water and membranes of phospholipids with varying acyl chain-lengths

Kamaya, Hiroshi; Kaneshina, Shoji; Ueda, I.

doi:10.1016/0005-2736(81)90280-7

Cited by 132 publications

(39 citation statements)

References 15 publications

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“…It was shown in earlier papers (Haydon et al 1977;Haydon & Hendry, 1982) that the cut-off in potency found for n-alkanes in the range n-pentane to n-decane correlates with a decrease in adsorption to a lecithin-cholesterol bilayer. It is consistent therefore that the absence of a cut-off for the n-alkanols up to n-decanol is paralleled by the maintained adsorption in this range (Hill, 1974;Jain, Gleeson, Upreti & Upreti, 1978;Kamaya, Kaneshina & Ueda, 1981). Partitioning between aqueous solution -3.11* Kamaya, Kaneshina & Ueda (1981) and dimyristoyl-, dipalmitoyl-and distearoylphosphatidylcholine Adsorption at n-dodecane-aqueous -3.12* Mitchell (1969) solution interface Aveyard & Haydon (1973) Blockage of the propagated action -2-88* Calculated from data in Seeman potential in sciatic nerve (1972).…”

Section: Resultssupporting

confidence: 62%

The action of alcohols and other non‐ionic surface active substances on the sodium current of the squid giant axon.

Haydon¹,

Urban²

1983

The Journal of Physiology

103

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SUMMARY1. The effects of several n-alkanols and n-alkyl oxyethylene alcohols, methyl octanoate, glycerol 1-monooctanoate and dioctanoyl phosphatidylcholine on the ionic currents and electrical capacity of the squid giant axon membrane have been examined.2. The peak inward current in voltage-clamped axons was reduced reversibly by each substance.3. For n-pentanol to n-decanol the concentrations required to suppress the peak inward current by 50 % were determined. From these data, it was estimated that the standard free energy per CH2 for adsorption to the site of action was -3 04 kJ mole-', as compared with -3-11 kJ mole-' for adsorption into phospholipid bilayers or an n-alkane/aqueous solution interface. 4. The membrane capacity at 100 kHz was not greatly affected by any of the test substances at concentrations which reduced the inward current by 50 %.5. Na currents under voltage clamp were recorded in intracellularly perfused axons before, during and sometimes after exposure to the test substances and the records were fitted with equations similar to those proposed by Hodgkin & Huxley (1952).6. Shifts in the curves of the steady-state activation and inactivation parameters (mo and h.o) against membrane potential, changes in the peak heights of the activation and inactivation time constants (Tm and Th) and reductions in the maximum Na conductance (gNa) have been tabulated.7. All of the test substances shifted the voltage dependence of the steady-state activation in the depolarizing direction and lowered the peak time constants for both activation and inactivation. The origins of these effects, and of the differences in the present results from those of the hydrocarbons (Haydon & Urban, 1983), have been discussed in terms of the physico-chemical properties of the two groups of substances and with reference to their effects on artificial membranes.

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Section: Resultssupporting

confidence: 62%

The action of alcohols and other non‐ionic surface active substances on the sodium current of the squid giant axon.

Haydon¹,

Urban²

1983

The Journal of Physiology

103

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“…Unfortunately, most previous determinations of n-alcohol partition coefficients have been for cholesterol-free lipid bilayers, and all of this work has been restricted to the lower n-alcohols. The most reliable and extensive data have been obtained by Hill (19,20) and by Kamaya et al (21) for fluid bilayers of dipalmitoyl lecithin. If we extrapolate their data from ethanol to the highest n-alcohols used (octanol and heptanol, respectively), we obtain an average partition coefficient for 1-decanol that is about twice the value for our cholesterol containing membranes.…”

Section: Discussionmentioning

confidence: 93%

Partitioning of long-chain alcohols into lipid bilayers: implications for mechanisms of general anesthesia.

Franks¹,

Lieb²

1986

Proc. Natl. Acad. Sci. U.S.A.

139

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Alcohols act as anesthetics only up to a certain chain length, beyond which their biological activity disappears.Although the molecular nature of general anesthetic target sites remains unknown, presently available data support the hypothesis that this "cutoff" in anesthetic activity could be due to a corresponding cutoff in the absorption of long-chain alcohols into lipid-bilayer portions of nerve membranes. To test this hypothesis, we have developed an extremely sensitive biological assay, based on inhibition of the light-emitting firefly luciferase reaction, which is capable of measuring lipidbilayer/buffer partition coefficients K for very lipid soluble compounds. Contrary to the hypothesis and reported data, we find a strictly linear increase in log(K) as the chain length increases [A(AG")CH2 = -3.63 kJ/mol] for the primary alcohols from decanol to pentadecanol, with no hint of a cutoff. The fact that alcohols continue to partition into lipid bilayers long after their biological activity has ceased is consistent with the view that the primary target sites in general anesthesia are proteins rather than the lipid-bilayer portions of nerve membranes.For nearly a century it has been known that alcohols can act as general anesthetics (1,2). As the chain length of an alcohol increases, so does its potency (-1/ED50 concentration, where ED50 is the dose for 50% effect) as an anesthetic. Eventually, however, anesthetic potency begins to level off, and a point is soon reached beyond which anesthetic activity disappears (the so-called "cutoff effect"). For the primary alcohols, general anesthetic potency levels off after about undecanol (C11) and completely disappears after tridecanol (C13) (3,4). Thus, while 1-dodecanol (C12) is among the most potent of all the alcohols, 1-tetradecanol (C14) is completely inactive. Although such behavior is consistent with protein mechanisms of general anesthesia (5), it presents a real problem for lipid theories. It has, however, been argued (4, 6, 7) that the observed cutoff in anesthetic potency is due to a corresponding cutoff in the ability of long-chain n-alcohols to partition into lipid bilayer portions of nerve membranes.Presently available data on the partitioning of radiolabeled long-chain alcohols into biological membranes (8) and lipid bilayers (6) do in fact support the hypothesis (4, 6, 7) that the higher n-alcohols are inactive simply because they cannot attain high enough concentrations in lipid bilayers. However, labeling techniques are notoriously unreliable when measuring large membrane/buffer partition coefficients, since the presence of very small amounts of water-soluble impurities can produce severe underestimates. We have now reinvestigated this problem by developing a technique, based on the inhibition of firefly luciferase light output by anesthetics (5, 9) in the presence of membranes, which can reliably measure membrane/buffer partition coefficients having values up to at least 10 million (when expressed as ratios of molar concentrations). PRINCIPL...

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“…Physiological assays determined that an aqueous concentration of 5 mM of chlf is enough to block nerve conduction [54,55]. The partition coefficient of chlf between water and a lipid membrane was measured for DPPC bilayers giving a value of 30 [56], which would correspond to a chlf concentration of 150 mM inside the membrane phase. According to the volume of our simulated membranes, a ratio of about 0.09 chlf molecules per lipid is required to induce anaesthesia.…”

Section: Discussionmentioning

confidence: 99%

Chloroform alters interleaflet coupling in lipid bilayers: an entropic mechanism

Reigada

Sagués

2015

J. R. Soc. Interface.

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The interaction of the two leaflets of the plasmatic cell membrane is conjectured to play an important role in many cell processes. Experimental and computational studies have investigated the mechanisms that modulate the interaction between the two membrane leaflets. Here, by means of coarsegrained molecular dynamics simulations, we show that the addition of a small and polar compound such as chloroform alters interleaflet coupling by promoting domain registration. This is interpreted in terms of an entropic gain that would favour frequent chloroform commuting between the two leaflets. The implication of this effect is discussed in relation to the general anaesthetic action.

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Partition equilibrium of inhalation anesthetics and alcohols between water and membranes of phospholipids with varying acyl chain-lengths

Cited by 132 publications

References 15 publications

The action of alcohols and other non‐ionic surface active substances on the sodium current of the squid giant axon.

The action of alcohols and other non‐ionic surface active substances on the sodium current of the squid giant axon.

Partitioning of long-chain alcohols into lipid bilayers: implications for mechanisms of general anesthesia.

Chloroform alters interleaflet coupling in lipid bilayers: an entropic mechanism

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